Akkermansia muciniphila and its membrane protein ameliorates intestinal inflammatory stress and promotes epithelial wound healing via CREBH and miR-143/145

Journal of Biomedical Science

Research

Ekta Pandey¹  Edward N. Harris¹  Linda Fatumoju¹  Kaichao Pan²  Rongxue Wu²  Qiaozhu Su³  Qihua Duan³  Szczepan Kaluzny³  Henry Wade³  Viswanathan Saraswathi⁴ 

[1] Department of Biochemistry, University of Nebraska-Lincoln, 68583, Lincoln, NE, USA;Department of Medicine, Section of Cardiology, University of Chicago, Chicago, USA;Institute for Global Food Security, School of Biological Sciences, Queen’s University Belfast, BT9 5DL, Belfast, UK;University of Nebraska Medical Center, 68198, Omaha, NE, USA;

关键词: Akkermansia muciniphila;    Amuc_1100;    CREBH;    microRNA-143/145;    Intestinal inflammatory stress;    Epithelial regeneration;    Wound healing;   

DOI  :  10.1186/s12929-023-00935-1

 received in 2022-12-27, accepted in 2023-05-30,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundThe intestinal epithelial barrier is the interface for interaction between gut microbiota and host metabolic systems. Akkermansia muciniphila (A. muciniphila) is a key player in the colonic microbiota that resides in the mucus layer, whose abundance is selectively decreased in the faecal microbiota of inflammatory bowel disease (IBD) patients. This study aims to investigate the regulatory mechanism among A. muciniphila, a transcription factor cAMP-responsive element-binding protein H (CREBH), and microRNA-143/145 (miR-143/145) in intestinal inflammatory stress, gut barrier integrity and epithelial regeneration.MethodsA novel mouse model with increased colonization of A muciniphila in the intestine of CREBH knockout mice, an epithelial wound healing assay and several molecular biological techniques were applied in this study. Results were analysed using a homoscedastic 2-tailed t-test.ResultsIncreased colonization of A. muciniphila in mouse gut enhanced expression of intestinal CREBH, which was associated with the mitigation of intestinal endoplasmic reticulum (ER) stress, gut barrier leakage and blood endotoxemia induced by dextran sulfate sodium (DSS). Genetic depletion of CREBH (CREBH-KO) significantly inhibited the expression of tight junction proteins that are associated with gut barrier integrity, including Claudin5 and Claudin8, but upregulated Claudin2, a tight junction protein that enhances gut permeability, resulting in intestinal hyperpermeability and inflammation. Upregulation of CREBH by A. muciniphila further coupled with miR-143/145 promoted intestinal epithelial cell (IEC) regeneration and wound repair via insulin-like growth factor (IGF) and IGFBP5 signalling. Moreover, the gene expressing an outer membrane protein of A. muciniphila, Amuc_1100, was cloned into a mammalian cell-expression vector and successfully expressed in porcine and human IECs. Expression of Amuc_1100 in IECs could recapitulate the health beneficial effect of A. muciniphila on the gut by activating CREBH, inhibiting ER stress and enhancing the expression of genes involved in gut barrier integrity and IEC’s regeneration.ConclusionsThis study uncovers a novel mechanism that links A. muciniphila and its membrane protein with host CREBH, IGF signalling and miRNAs in mitigating intestinal inflammatory stress–gut barrier permeability and promoting intestinal wound healing. This novel finding may lend support to the development of therapeutic approaches for IBD by manipulating the interaction between host genes, gut bacteria and its bioactive components.

【 授权许可】

CC BY   
© The Author(s) 2023

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